Author(s): Riccardo G Borroni
acute generalized exanthematous pustulosis; cutaneous adverse drug reaction; drug-induced skin injury; drug reaction with eosinophilia and systemic symptoms; HLA; hypersensitivity syndrome; pharmacogenetic; Stevens-Johnson syndrome; toxic epidermal necrolysis
In daily clinical practice, different responses to the same pharmacological treatment, in terms both of efficacy and toxicity, are common, even among subjects with apparently homogeneous clinical and demographic features. Adverse drug reactions (ADRs) are defined as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product; adverse effects usually predict hazard from future administration and warrant prevention, or specific treatment, or alteration of the dosage regimen, or withdrawal of the product" [1 ]. It is estimated that ADRs cause about 6% of all hospital admissions, and their prevalence in inpatients is up to 15% [2-4 ]. With over 100,000 deaths per year in the US and the UK alike, ADRs represent the fourth to sixth most common cause of death [2-4 ] and account for 5-9% of hospital admission costs [5 ].
Schematically, ADRs can be classified into two types. 'Type A' reactions (whereby 'A' also may stand for 'augmented') are related to the mechanism of action of the drug, usually dose-dependent and therefore predictable. Examples of type A cutaneous ADRs include phototoxic reactions, hyperpigmentation, toxicity toward hairs or skin of antineoplastic chemotherapy and effects on skin and appendages of corticosteroids and hormones [6 ]. 'Type B' (also referred to as 'bizarre' or idiosyncratic) reactions, less common, are thought to be unrelated to the known pharmacokinetics when administered in the usual therapeutic doses to a patient in ideal condition, not as dependent on dose, and generally immune-mediated. Due to their low incidence, type B reactions are often observed only after post-marketing use in large patient populations [ 3 ]. In addition, type B reactions are often severe and occasionally life threatening, explaining their withdrawal from the market.
Drug responses may at least in part be influenced by age, dose, hepatic and renal function, pregnancy, concomitant viral infection, drug-drug and drug-food interactions, immunosuppression, comorbidity and lifestyle. All these factors can also change over time in the same individual. Genetic polymorphisms, that is, naturally occurring variations in the DNA sequence that exist in normal individuals with a frequency [greater than or equal to]1%, may have consequences on function and/or expression of genes involved in pharmacokinetics and pharmacodynamics [7 ]. In addition, genetic polymorphisms may determine changes in expression or function of genes implicated in the immune response, such as the HLA genes, that orchestrate specific types of immunologically mediated ADRs.
In this article, the aspects of clinical dermatology relevant to the genetic susceptibility to cutaneous ADRs will be reviewed. Thanks to the recent advances in pharmacogenomics of cutaneous ADRs, more of type B reactions, traditionally considered unpredictable, are now known to be related to host genetic factors, and thus preventable.
Drug-induced skin injury
The skin, either as the exclusive target or part of a multisystem impairment, is the organ most frequently involved in ADRs....